Knoevenagel with acetonitrile

The Knoevenagel reaction between o-hydroxyaryl aldehydes and ketones and substituted acetonitriles affords high yields of 3-substituted coumarins in aqueous alkaline media <96H(43)1257>, whilst 4-hydroxycoumarins have been elaborated to pyrano [3,2-c]benzopyran-5-ones by reaction with aromatic aldehydes and malononitiile <96P148>. The imine (10) resulting from the complex reaction of o-hydroxyacetophenone with malononitrile undergoes a 1,5-tautomeric shift in solution <96JCS(P1)1067>. 

Indole derivatives such as dihydroindolone are scaffolds of potentially biological interest. Thus, the development of such functionalized skeletons has been approached by a MCR involving cyclic 1,3-diketones, cyclohexyl isocyanide, aromatic aldehydes, and ammonium acetate in the presence of catalytic amount of KHSO4 in refluxing acetonitrile (Scheme 30) [117]. hi this strategy, the imine derived from the Knoevenagel adduct reacts with cyclohexyl isocyanide to give the... 

The presence of substituents in the vinyl group of vinylthiophenes modifies reactivity. The vinylthiophene 70, obtained via a Knoevenagel condensation from 2-thienylacetonitrile and acetaldehyde as an 87 13 E-Z mixture, reacted with DMAD (11 days at reflux in acetonitrile) to give the adducts 71, 72, and 73 (87T991). The surprising compound 73 could be formed through the ene intermediate 74. 

The method of choice for the synthesis of unsaturated arylsulfones is the Knoevenagel condensation of arylsulfonylalkanes with aldehydes. The condensation between aldehydes and phenylsulfonyl acetonitrile, has been performed in the presence of various solid base catalysts (MgO, Cs-exchanged X zeolite, Al-Mg mixed oxide, and aluminophosphate oxynitride) at 373 K in the absence of solvents.1641 The most active catalyst for this transformation was the aluminophosphate oxynitride, but MgO and the Al-Mg mixed oxide also were found to have excellent activity, yielding the Knoevenagel adduct in yields of 86 and 71 %, respectively, after 2 h in a batch reactor. 

The general approach can be enlarged and conditions for condensation made milder by the use of further-activated esters, thus condensation with methyl nitroacetate produces 3-nitro-coumarins, condensations with Wittig ylides " allow orffto-hydroxyaryl ketones to be used ° and the use of diethyl malonate (or malonic acid ) (a 3-ester can be removed by hydrolysis and decarboxylation ), malononitrile, ethyl trifluo-roacetoacetate, or substituted acetonitriles in a Knoevenagel condensation, produces coumarins with a 3-ester, 3-trifluoroacetyl, " 3-cyano, or 3-alkyl or -aryl substituent. Condensation with IV-acetylglycine generates 3-acetylamino-coumarins. ... 

In addition to natural products, a multitude of biologically active unnatural compounds have also been synthesized using the Knoevenagel condensation. A few recent examples are given here. In an attempt to obtain enantiomerically pure 1,4-dihydropyridines as calcium channel antagonists, (/ )-sulfmylpropan-one (320) was condensed with 2-chlorobenzaldehyde in acetonitrile with piperidine as catalyst to provide exclusively the ( )-benzylidene compound (321). Formation of the (5)-l,4-dihydropyridine (323) as a... 

The Knoevenagel reaction has been carried out between aldehydes and acetonitrile in water. Thus, salicylaldehydes react with malononitrile at room temperature in the heterogeneous aqueous alkaline medium to give... 

A diastereoselective synthesis of cyclopropanes combines an aryl acetonitrile, ArCH2CN, with an aldehyde, RCHO, to give 100% cis-product (116) as a racemic mixture of enantiomers. " The one-pot reaction shows yields of 45-93% covering a wide range of substrates Ar includes 3-pyridyl and 2-thiophenyl, and the aldehyde can be aromatic or aliphatic. The reaction sequence consists of a Knoevenagel condensation followed by a Corey/Chaykovsky cyclopropanation. 

The cyanovinylene moiety is constructed by the Knoevenagel condensation of a suitable aldehyde with an aryl acetonitrile derivative using potassium r-butoxide. EDOT carboxaldehyde was prepared by the Vilsmeier formylation of EDOT with POC1.J and DMF while EDOT acetonitrile was prepared by the Ni(acac)2 catalyzed coupling of EDOT-ZnCl with bromoacetonitrile as shown below 8). 

In the first version of this reaction, an a-sulfanyladehyde or -sulfanylketone 5a is treated with a-aetivated acetonitrile 6 in the presence of a basic catalyst (usually triethylamine or piperidine). Reaction performed in the solvents like methanol, ethanol or DMF at 50 °C takes place in two snbsequent steps -Knoevenagel-Cope condensation [32, 33] and intramolecnlar ring closnre of formed sulfanyl substitnted o y nnsatnrated nitrile 8 (Scheme 3). 

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